Pharmaceutics 2

PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

INTRODUCTION TO PHARMACEUTICAL MAUFACTURING no testing of raw materials. Only in the

finish product.
MANUFACTURING (AO NO. 43 S. 1999) – LAW OF
MANUFACTURING PHARMACY targets the manufacturing (primary,
 The complete set of activities to produce a drug that secondary or tertiary)
comprise production and quality control from
dispensing of materials to the release for distribution of o Advantages: time efficient, can save
the finished product. money and effort
 This includes designing, testing, pre-formulation,
formulation, quality control, preparation of raw DRUG ESTABLISHMENTS
materials and etc. An organization or company involved in the manufacture,
 Drug – diagnose, mitigate, treat, and cure, prevent importation, repackaging and distributions of drugs and
(DMITRI CUPRE) medicines.
PHARMACEUTICAL MANUFACTURING Drug  Any establishment engaged in operations
 The manufacture, propagation, preparation and Manufacturer involved in the production of drugs.
processing of a drug product in a large scale.
 The making by physical, chemical, biological or any  Proprietary/generic
other procedure of any article that meets the definition manufacturer – Ritemed, Rhea,
of drugs. Unilab (Proprietary)
 The manipulation, sampling, testing or control  Involves only with the production of
procedures applied to the final product or any other generic drug products
part of the process.  Ethical manufacturer – Rx drugs/
 The packaging, repacking or changing the container, prescribed drug
wrapper or label of any drug package in preparation  Biological manufacturer –
for its distribution from the manufacturer to the final vaccines, sputnik by Russian
user. company
 Mass production of drug products.  Veterinary products
manufacturer – animals
Pharmaceutical Extemporaneous Compounding  Medicinal chemical
Manufacturing manufacturer – reagents,
• Large-scale • Small scale preparation of drug products alcohols, disinfectants
preparation of • Prescription order  -Toll/Contract manufacturer
drug products • Specific for a particular patient. Drug Imports or exports raw materials, active
•Manufacturing • Done in community pharmacy and Distributor ingredients or finished products for its own
order hospital pharmacy use or for wholesale distribution on
• For General • E.g.: Paper tablets wholesale basis
public use Drug distributor (wholesaler)

Produce raw materials, active ingredients

TYPES OF PHARMACEUTICAL MANUFACTURING and or finished product from local
 produces API and excipients, produce establishment or for the local distribution on
Primary raw materials wholesale basis.
manufacturing Targets the secondary manufacturing Drug Trader  Registered owner of the drug product but
Secondary  production of finished dosage form or subcontracts toll manufacturer of such
manufacturing drug product from API and excipients, products to a licensed manufacturer.
receive and order from primary May also engage in distribution and or
manufacturer. marketing of products.
Targets the general public
Tertiary  production of packaging, labelling, and
manufacturing repacking of bulk finished product, no
direct contact with API and excipients
Toll  an arrangement whereby a competent
Manufacturing company processes raw materials, semi-
finished goods, and packages product for
another company, used by facilities that
cannot produce their own medicine by
hiring another manufacturing firm.

REMELLETE, LESLIE ANN T. 1

Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

DEPARTMENT IN A DRUG ESTABLISHMENT

GENERAL DESIGN AND CONSTRUCTION FEATURES OF
(1) Research and development department PHARMACEUTICAL PLANT
• Formulates and develops new product, improves
existing products.
• Does pharmaceutical, chemical and physiological PREMISES
researchers • The premises for manufacturing shall be suitable size, design,
• they also do toxicity and allergenicity testing construction and location to facilitate proper operation,
• 3 facilities: Library, Animal house, Pilot plant cleaning and maintenance.
(2) Production department • The individual working area shall be adequate so that any risk
• Manufacture drug products according to schedule of confusion, cross contamination and other mistakes that will
(Manufacturing order) adversely affect the quality of drugs and devices will be
• Warehousing, Inventory control, Storage avoided.
(3) Quality control and quality assurance department LOCATION, CONSTRUCTION, DESIGN & LAYOUT
• Ensure that all operations involved meet the • Shall be located and protected against contamination from
standards of quality, purity, safety and efficacy. the environment
• Assures the compliance to cGMP • Shall be constructed and maintained to protect against
• “Heart and Soul” of a drug manufacturer weather, flood, ground seepage and the access and harboring
• Sampling, testing and assaying of drugs of vermin, rodents, birds, insects or other animals.
(4) Marketing department • In determining the design and layout of premises,
• Promotes maximum volume of sales of products consideration should be paid to:
(advertisement) • Compatibility of other manufacturing operations that may
• Monitors product status, consumers behavior and carried out in the same or adjacent premises.
market trends. • Allow production to take place in areas connected in logical
(5) Engineering department order according to the sequence of the operations and to the
• Install maintains and repairs equipment’s and requisite cleanliness level.
facilities. • Adequacy of working space, which shall allow orderly and
• Ensure the safety of the plant and logical placement of equipment and materials to suit the
employees/personnel. operation, efficient flow of work, effective communication and
supervision to avoid crowding and disorder.
(6) Purchasing department
• Avoid the use of production areas as general traffic for
• Purchases, receives and inventories of supplies
personnel or materials or for storage other than the materials
(7) Medical department
in process.
• Does annual or quarter physical and medical
examination of employees and applicants.
• Does the clinical studies.
• Prepares product inserts and literature.
• Publishes company’s newsletter/organ
(8) Regulatory Affairs Department
• Responsible for the processing of all regulatory
processes.
• Responsible for product registration.

ORGANIZATIONAL STRUCTURE OF
PHARMACEUTICAL COMPANY

The layout of rooms, corridors and spaces shall provide for

logical movements of materials and personnel with minimal
traffic for operations to be carried out in defined area and to
avoid cross-contamination. The design and layout shall fulfill
the following requirements:
• Prevent risk of mix-up between different drugs or their
components, cross- contamination and omission of any
production step.
• Penicillin’s shall be produced only in separate buildings, with
separate air handling facilities.
• Cephalosporin shall be produced in separate buildings with
separate air handling facilities.

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Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

• In all manufacturing rooms, air supply and air exhaust • Toilets should not be opened directly to production areas
points shall not be so close or so disposed as tor resistor and shall have adequate supply of water and ventilation.
negate the supply of clean air to worksites and or movement • Experimental animals shall be house in a separate
of product dust or other contaminant away from worksite. building.
• Air handling facilities for the production of cytotoxins shall • There shall be separate or defined areas for the firm’s
be appropriate. operations to prevent contamination or mix-ups as follows:
• Processing of materials for drug products shall be
separated from the production of non-drug products. 1. Gowning/Change rooms for all personnel
• Separate space for cleaning mobile equipment and o Connected to the production area
storage of cleaning materials o Wearing of PPE (Personal Protective
• Locker/gowning room shall be directly connected to but Equipment) such as mask, foot sock, hair
separated from the processing areas. net, lab gown)
• Toilets should not be opened directly to production areas 2. Receiving of starting materials (incoming goods
and shall have adequate supply of water and ventilation. quarantine)
• Experimental animals shall be house in a separate o YELLOW/ORANGE- under quarantine (to
building. avoid cross-contamination and testing
prior to mass production)
• In all manufacturing rooms, air supply and air exhaust 3. Sampling Room
points shall not be so close or so disposed as tor resistor o For sampling of deliveries for starting
negate the supply of clean air to worksites and or movement materials
of product dust or other contaminant away from worksite. 4. Storage for approved materials
• Air handling facilities for the production of cytotoxins shall o GREEN-approved materials/products for
be appropriate. mass production
• Processing of materials for drug products shall be 5. Storage for Rejected materials
separated from the production of non-drug products. o RED-rejected materials
• Separate space for cleaning mobile equipment and o Rejected materials will be return to the
storage of cleaning materials supplier
• Locker/gowning room shall be directly connected to but 6. Laboratories
separated from the processing areas. o R & D department, QA &QC department,
• Toilets should not be opened directly to production areas Medical department
and shall have adequate supply of water and ventilation. 7. Weighing/ dispensing of materials
• Experimental animals shall be house in a separate  Dispensing in manufacturing company
building.  The act of weighing, measuring, preparing raw
materials (in manufacturing)
 Dispensing in pharmaceutical care
 Release of medication

ASEPTIC PROCESSING

 Floors, walls and ceiling of smooth, hard surfaces

that are easily cleanable
 Temperature and humidity controls
 An air supply filtered through high-efficiency
particulate air filter (HEPA) under positive pressure
regardless of whether flow is laminar or non-
laminar systems for monitoring environmental
conditions
 System for cleaning and disinfecting the room and
equipment to produce aseptic conditions
 A system for maintaining any equipment used to
Additional info only: control the aseptic condition.
 HEPA is a type of pleated mechanical air filter. It is
an acronym for "high efficiency particulate air 8. Lighting
[filter]. This type of air filter can theoretically  adequate lighting shall be provided in all areas
remove at least 99.97% of dust, pollen, mold,
bacteria, virus and any airborne particles with a
size of 0.3 microns (µm).

REMELLETE, LESLIE ANN T. 3

Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

VENTILATION, AIR FILTRATION,  Finishes with vinyl or epoxy-sealing coat provides

AIR HEATING AND COOLING a continuous surface free from all other
a)  Adequate ventilation shall be provided holes/crevices.
b)  Equipment for adequate control over air  Should be exhausted adequately so that the heat
pressure, microorganism, dust, humidity, and and humidity will be removed for the comfort of
temperature shall be provided when personnel.
appropriate for the manufacture, processing,  Adequate sink and counter space must be
packing, or holding of a drug product. provided.
c)  Air filtration systems, including pre-filters and  Must be cleanable and microbial load must be
particulate matter air filters, shall be used when monitored and controlled.
appropriate on air supplies to production areas.
If air is recirculated to production areas,
measures shall be taken to control recirculation COMPOUNDING AREA
of dust from production. In areas where air  In this area the formula is compounded, and although it
contamination occurs during production, shall is not essential that this area must be aseptic, control of
be adequate exhaust systems or other systems microorganisms and particulates should be more stringent
adequate to control contaminants than in the materials support area.
d)  Air-handling systems for the manufacture,  Cabinets and counters should preferably be
processing, packing of penicillin shall be constructed of stainless steel
completely separate from those for other  Fit snugly to walls and other furniture
products for human use.  Ceiling, walls and floor should similar to those for
PLUMBING the material support area.
a)  Potable water shall be supplied under
continuous positive pressure in a plumbing ASEPTIC AREA
system free of defects that could contribute DISPENSING AREA (defined area)
contamination to any drug product. Potable  Requires construction features designed for maximum
water shall meet the standards prescribed in the microbial and particulate control.
Environment Protection Agency’s Primary  Ceiling, walls, and floors must be sealed
Drinking Water Regulations set forth in 40 CFR  All counters should be constructed od stainless
part 141. steel and hung from the wall
 Light fixtures, utility service lines and ventilation
• Water not meeting such standards shall not be fixtures must be recessed in the walls of the ceiling.
permitted in the potable water system.  Tanks containing the compounded product should
b)  Drains shall be of adequate size and where remain outside the aseptic area
connected directly to a sewer, shall be provided  Product fed into the area through the hose lines
with an air break or other mechanical device to  Large mechanical equipment should be housed as
prevent back-siphonage. possible within stainless steel cabinet
 Mechanical parts that will contact the parenteral
CLEAN ROOM CLASSIFICATIONS product should be demountable.
Clean room designations assigned by the International  the personnel entering the aseptic area should enter
Society of Pharmaceutical Engineers (ISPE) through AIRLOCK ROOM. They should also wear STERILE
COVER (ex. PPE) prior to entering.

Additional info only:

An airlock is a transitional space that typically has two
doors in series to separate a controlled environment (such
as cleanroom, lab, operating room, or isolation room) from
a corridor, or vice versa. The two doors should be
interlocked to avoid being opened at the same time.

 Movement within the room should be minimal and in &

out movement should be restricted during filing procedure.

MATERIALS SUPPORT AREA

 Constructed to withstand moisture, steam, detergents
and is usually a CLASS 100,000 clean room
 Ceiling, walls and floor should be constructed of
impervious materials

REMELLETE, LESLIE ANN T. 4

Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

INTRODUCTION TO PRODUCT Stable/acceptable shelf-life

LIFE CYCLE MANAGEMENT Clinical trial process robust and can
At the end of the lesson: be scaled up
 Identify the drug development drivers, challenges,
REGULATORY Quality of data/documentation
risks and rewards.
MANUFACTURING Manufacturable
 Enumerate the major hurdles to a successful
product sale and registration. Able to pass pre-approval
 Define product life cycle inspection
 Describe the current trends in the pharmaceutical MARKETING Competitive Meets customer needs
industry. /COMMERCIAL Value for money Commercial return

PRODUCT LIFE CYCLE (PLC) CHALLENGES IN PHARMACEUTICAL

 Is considered as the MAJOR CONCERN of the R& D PRODUCT LIFE CYCLE MANAGEMENT
department because its main objective is DRIVING FORCES:
“converting ideas into candidate drugs for  NEW DISCOVERIES BE FREQUENTLY BROUGHT TO
development” THE MARKET
 GETTING TO THE MARKET QUICKLY
OBJECTIVE: (PHARMACEUTICAL R&D
1. NEW DISCOVERIES BE FREQUENTLY BROUGHT TO THE
“converting ideas into candidate drugs for development” MARKET
OBJECTIVE: (PRODUCT DEVELOPMENT) RISK:
“converting candidate drugs into products for registration  Cost of drug discovery and development to bring a New
and sale” Chemical Entity (NCE) to the market is ever increasing
MAJOR HURDLES TO SUCCESSFUL (costly)
PRODUCT REGISTRATION AND SALE  Delay on product registration and launching
 10 to 12/15 years estimated (from drug
discovery to product launching)
ACTIVITY REQUIREMENTS
 Treatment IND (investigational new drug) is a
RESEARCH Novel compound (patentable?) mechanism for providing eligible subjects with
Novel biological mechanism investigational drugs for the treatment of
(patentable?) serious and life-threatening illnesses for which
Meet Unmet medical needs there are no satisfactory alternative
 A new drug can be said to treatments.
CHALLENGE:
fulfill an unmet medical
 Improving process to bring new products to market that
need if it addresses a can accelerate product development while lowering
condition whose treatment operational costs
or diagnosis is not  Improving processes to bring new products to market
adequately addressed by that can accelerate product development while lowering
existing treatments. operational costs
 This can mean either that 2. GETTING TO THE MARKET QUICKLY (cross-cutting)
the drug treats a condition RISK:
for which no other  Minimum development programme and cutting corners
to fast track to market
treatment exists, or that it
CHALLENGE:
confers some benefit that  Accelerating and optimizing drug discovery and
existing treatments do not. development which generate sufficient information to
 Eg: New or improved effect enable sound decisions on the selection of a candidate
on a treatment outcome, drug for development as well as to develop dosage forms
decreased toxicity, or which are “fit for purpose” at various stages of
fewer interactions with development
other drugs.
Potent and selective SEVERAL FACTORS CONTRIBUTED TO
SAFETY High margin of safety LENGTHENING DEVELOPMENT
1. Increase in the preclinical phase (takes 4-6 years)
Non-toxic (not carcinogenic,
to select the candidate drug
teratogenic, mutagenic, etc.)
 Candidate drug to nomination for
CLINICAL Tolerable side-effects profile
regulatory submission takes 6-8 years
Efficacious especially for chronic conditions.
DRUG PROCESS Bulk drug can be synthesized/scaled
2. Increase in the duration of the clinical and
up regulatory period required for marketing
PHARMACEUTICAL Acceptable formulation/pack approval.
(meets customer needs)
Drug delivery/product performance
acceptable

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Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

WAYS TO REDUCE DEVELOPMENT COST PRODUCT LIFE CYCLE MANAGEMENT

1. Selectively screen and eliminate compounds
earlier in the drug development process based on PRODUCT LIFECYCLE
the results from small-scale, less expensive studies - Refers to all phases in the life of a product from initial
in man and progress fewer, more certain development through marketing until product’s discontinuation.
compounds for later clinical phases. - From discovery to discontinuation (final withdrawal)
2. Re-evaluation and subsequently streamlining the 1. INITIATION
development process. 2. PLANNING
 By introducing more effective clinical 3. EXECUTION
programs 4. CLOSING
 More efficient data reporting systems Note:
 Forward planning For a drug product to be reintroduce back to the market,
 Conducting multiple activities in parallel. significant changes must be observed such as: (changes in)
Additional info only: 1. packaging
Streamlining is the process used to simplify or eliminate 2. dosage form
unnecessary work-related tasks to improve the efficiency 3. labeling
of processes in businesses or organizations. 4. Tablet shape
5. Tablet color
SIGNIFICANT RISK ASSOCIATED WITH DOING A
MINIMUM DEVELOPMENT PROGRAM AND CUTTING - In recent years, the pharmaceutical industry has faced
CORNERS TO FAST TRACT TO THE MARKET: declining R&D productivity because of the rapidly
1. Post-launch, the cost of a retrospective fix due to changing healthcare landscape and there is a fierce
poor product/process design and/or development competition from the generics resulting in a lower
can be extremely high. growth and profit margin.
2. Financial cost from work in product/process - However, the industry is now looking now for a HOLISTIC
redevelopment, manufacturing and validation, APPROACH to improve the process of bringing new
technical support, regulatory and sales and products to the market that can accelerate product
marketing (due to a product recall) development while lowering the operational cost.
Additional info only:
A drug/product recall is the most effective way to protect Improving an already existing product through: (PLM)
the public from a defective or potentially harmful product.  Improving formulation
A recall is a voluntary action taken by a company at any  Excipients
time to remove a defective drug product from the market.  Less side effects
3. It may affect the market share and the company’s  Change dosage forms
relationship with the regulatory authorities and its  Medicine size
credibility with customers.  Marketing aspect (advertisement, social media)

PRODUCT LIFECYCLE MANAGEMENT (PLM) FIGURE 1.2 PRODUCT LIFECYCLE MANAGEMENT (CASH FLOW)
Concept:
 Any reduction in total time-frame of drug
discovery to market should improve the
company’s profitability
 In a highly competitive market, product lifetimes
are being eroded due to the:
Pace of introduction of competitor products
The rapid introduction of generic products
when patients expire and moves to over-
the-counter (OTC) status
Note: Holistic approach to the challenges mentioned above is
to Focus on Product Lifecycle Management (PLM)

PRODUCT LIFECYCLE MANAGEMENT (PLM)

Concept:
 To maximize the early growth of the product on the
market, sustain peak sales for as long as the 20 years- maximum patency of a product
product is in patent and delay the post-patent
expiry decline for as long as possible.
 RE-INTRODUCTION of drug product back to its
peak in the market.

REMELLETE, LESLIE ANN T. 6

Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

PRODUCT LIFE CYCLE MANAGEMENT CURRENT TRENDS IN THE PHARMACEUTICAL

INDUSTRY
STRATEGIES - Increasing competition and threats to pharmaceutical
1. Ensure the best patent protection in order to achieve the industry with respect to maintaining continued sales
longest possible market exclusivity growth and income mean that successful companies going
2. To introduce new indications, formulations, manufacturing forward will be those which have a portfolio of products
processes, devices and general technology which are capable of showing volume
patent protected, to extend the life of the product and - The cost of drug discovery and development is escalating
maintain revenue because there are no easy targets left and the cost of
development and goods sold is increasing
FIGURE 1.1 PRODUCT LIFE CYCLE CURRENT TRENDS IN THE PHARMACEUTICAL
INDUSTRY
1. SOURCE OF DRUGS
- From Low Molecular weight chemical to a more
complex macromolecule (biologicals)
- Some of these compounds have been derived from
biotechnological process to produce biotechnological
medicinal products that fight infection and disease
- ex: vaccines (covid vaccines)
2. SOPHOSTICATED DRUG DELIVERY SYSTEMS
(cont.)
Examples
1. Electrophoresis
- Uses low level electrical energy to assist the
transport of drug across the skin
- Could be particularly useful for delivery of
peptides and proteins which aren’t adequately
transported by passive transdermal therapy
- Drug absorption rate is every rapid and more
controlled compared with passive diffusion
across the skin
- Addresses the problem of poor drug absorption
1. STRATEGIC RESEARCH and limitations of conventional drug delivery
- Class 1 product recall (more serious) such as adverse
side effects, serious health problems
- Talks about the API
2. EXPLORATORY RESEARCH
- involves in-vitro studies
- involves characterization of candidate drug
- physical and chemical strategy/characterization
3. CANDIDATE SELECTION
- Involves in-vitro studies
- involves characterization of candidate drug 2. Breathe-actuated aerosol
- biological, physical and chemical - Designed to coordinate Drug delivery with
strategy/characterization (pharmacology, patient’s inhalation to achieve this
toxicology) - This improvement in inhaler technology to
4. Exploratory development ensure a more efficient delivery to the lungs, with
- last stage in preclinical study/trial minimal drug deposition in mouth and trachea
- animal testing
- “a new drug doesn’t have to be new”
- PRODUCT MODIFICATION/IMPROVEMENT
- Class 3 product recall (less-serious)
- PRECLINICAL STUDIES/PREFORMULATION
- Talks about compatibility of API to the excipients
- Drug designing, biopharmaceutics,
pharmacokinetics, safety and efficacy determination

REMELLETE, LESLIE ANN T. 7

Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

3. Bio-erodable polymers
- Can be implanted/injected within body to
administer drugs from a matrix which can be
formulated to degrade over a long duration from
one day to six months and don’t require retrieval
- Addresses the “Non-compliance of patients and
inaccurate targeting of therapeutic agents”

3. MORE COMPREHENSIVE DICUMENTATION TO

DEMONSTRATE COMPLIANCE cGMP & cGLP

cGMP –Current good manufacturing practices

cGLP -Current good laboratory practices

 To demonstrate systems and procedures have

been validated. It’s for more information required
for a regulatory submission with little flexibility for
changes once submitted
 Therefore, pressure is for a company to submit
early and develop product “right first time

REMELLETE, LESLIE ANN T. 8

Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

PHARMACEUTICAL QUALITY SYSTEMS  To minimize quality variations or defective

Topic outline: products quality, control is necessary that
a. Quality Risk Management makes use of standards and specifications.
b. Contamination/Cross Contamination Prevention  These must cover the formula, raw materials
c. Good Documentation Practice specification, standard operating procedure
d. Good Quality Control Laboratory Practice (SOP), finished product specification,
e. Self-Inspection packaging, material standard and testing
QUALITY RISK MANAGEMENT methods. formula, raw materials
specification. etc –embedded in cGMP
 Compliance with current good manufacturing guideline
practices (cGMP), medicines regulatory activities  Formula, raw materials specification...etc-
and inspections, together with supply chain embedded in cGMP guidelines
controls throughout the product life-cycle, provide  However, where control is less effective,
good assurance that risks are largely controlled. patients may be put at risk through the
 Quality must be built or produced into the product, production of medicines of inadequate quality.
not only tested or inspected. (risks may proceed despite following all the
guidelines)
QUALITY
 Refers to the combination of attributes or QUALITY RISK MANAGEMENT (QRM)
characteristics of a product, when compared to a  Is the overall and continuing process of
standard, serves as a basis for measuring the appropriately managing risks to product quality
uniformity of the product and determines its throughout the product’s life cycle in order to
acceptability. optimize its benefit-risk balance.
 Quality attributes/characteristics are subject to  It is a systematic process for the assessment,
variations which may lead to errors producing control, communication and review of risks to the
defected products. quality of the medicinal product. It can be applied
GENERAL SOURCES OF PRODUCT QUALITY VARIATION both proactively (before manufacture) and
Involves 4 Ms: (Materials, Machine, Methods, Men) retrospectively (after manufacture).
ULTIMATE OBJECTIVE FOR A TOTAL CONTROL OF QUALITY:
MATERIALS (components)  Attainment of perfection in meeting specifications
variation in suppliers for a product with high-quality
variation in same substances  To have a zero-defect product
variation within a batch production
variation between batches in same supplier
 QRM exists in Pharmaceutical company and
MACHINE (equipment) MRAs (medicines regulatory authorities) to
variation from same process protect patients in terms of quality, safety and
difference in adjustments efficacy of medicines.
difference in calibration of equipment  The Medicines Regulatory Authorities (MRAs) is
difference in age of equipment the body in charge of coordinating and overseeing
improper caring of equipment the pharmaceutical sector for the purpose of
protecting public health. (additional info only)
METHODS (procedure)
Inexact procedure QRM principles can be applied to both MRAs and
Inadequate procedure Pharmaceutical Manufacturers
Negligence by chance; failure to follow MRAs MANUFACTURER
procedures Systematic and structured Design, development, manufacture
planning of reviews and and distribution, i.e. the life cycle of a
critical step- step that even when a little is not done right, it inspections that are risk- based. pharmaceutical product. QRM should
will result to product/ quality variation The submission review and be an integral element of the
inspection programs can also pharmaceutical quality system (QS).
MEN (personnel) operate in a coordinated and
synergistic manner. APPLICATION OF QRM:
Improper working condition  from the new chemical
Inadequate training APPLICATION OF QRM: entity
Inadequate understanding of work  After the product  starts at the strategic
has been research (based on PLM)
Dishonesty commercialized
Fatigue  Submission of IND
Carelessness (investigational new
drug) application

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PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

 The level of QRM activity and the density of

associated documentation will evolve as the RISK MANAGEMENT
product progresses from early development  The process of identifying, assessing and
through to routine production. controlling threats to an organization’s capital and
earnings.
PRINCIPLES OF QUALITY RISK MANAGEMENT
1. The evaluation of the risk to quality should be INVOLVES:
based on scientific knowledge and ultimately
linked to the protection of the patient.  Risk assessment
2. The level of effort, formality and documentation of -A systematic process of organizing information to
the QRM process should be commensurate with support a risk decision to be made within a risk
the level of risk (↑↑RISKS= ↑↑EFFORTS, FORMALITY management process.
& DOCUMENTATION) -Consist of identification, analysis, and evaluation
Note: of risk associated with exposure to those hazards
It is not always appropriate nor always necessary to use a a. Risk identification
formal risk management process (using recognized tools  The systematic use of information to identify
and/or internal procedures, e.g. standard operating potential sources of harm (hazards) referring to
procedures (SOPs). The use of an informal risk the risk question or problem description.
management process (using empirical tools or internal b. Risk analysis
procedures) can also be considered acceptable but only use  The estimation of the risk associated with the
when level of risk is MINIMAL. identified hazards.
c. Risk evaluation
In addition to the two principles above, the following  The comparison of the estimated risk to given risk
principles are also part of the QRM methodology: criteria using a quantitative or qualitative scale to
determine the significance of the risk.
 When applied, processes using QRM  Risk control
methodologies should be dynamic, iterative and  The sharing of information about risk and risk
responsive to change. (case by case response to management between the decisionmaker and
risks) other stakeholder
 The capability for continual improvement should  There is subareas risk reduction and risk
be embedded in the QRM process. (improvements acceptance
in risk management)  Risk review
 Review or monitoring of output or results of the risk
FIGURE 1. OVERVIEW OF A TYPICAL QUALITY RISK management process considering (if appropriate)
MANAGEMENT PROCESS new knowledge and experience about the risk.
 Ex: phase 4 clinical trial (POST-MARKETING
SURVEILLANCE)  monitoring & review of events

QUALITY RISK MANAGEMENT PROCESS

1. Initiating a QRM process
 QRM activities should be performed using
systematic processes designed to coordinate,
facilitate and improve science-based decision-
making with respect to risk.

The possible steps to be taken in initiating and planning a

QRM process might include the following:

 define the problem and/or risk question, including

pertinent assumptions identifying the potential for
risk;
 assemble background information and/or data on
the potential;
 hazard, harm or human health impact relevant to
the risk assessment;
 identify a leader and the necessary resources;
 specify a timeline, the deliverables, and an
appropriate level of decision-making for the risk
management process.

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■ microbial limits, where applicable;

■ premises;
1.1 Personnel involved in QRM ■ equipment;
 The implementing party, i.e. the pharmaceutical ■ packaging;
manufacturer or regulatory authority, should ■ sanitation and hygiene;
assure that personnel with appropriate product- ■ personnel (human error);
specific knowledge and expertise are available to ■ utilities;
ensure effective planning and completion of QRM ■ supply chain (pharmacy, distributor)
activities.
 This may be best accomplished by assembling a  The output of a risk assessment is either a
multidisciplinary team quantitative estimate of risk (numeric probability)
 The personnel appointed should be able to: or a qualitative description of a range of risk (e.g.
 conduct a risk analysis; high/ medium/low)
 identify and analyze potential risks;  The scoring system and trigger points for
 evaluate risks and determine which ones mitigating action are subjective so the rationale for
should be controlled and which ones can be score categorization should be defined in as much
accepted; detail as possible.
 recommend and implement adequate risk
control measures; 3. Risk control
 devise procedures for risk review, monitoring  is a decision-making activity designed to reduce
and verification; and/or accept risks. It usually occurs after risk
 consider the impact of risk findings on related assessment, and at a fundamental level its
or similar products and/or processes purpose is to reduce the risk to an acceptable
1.2 Knowledge of the product and process level.
 Personnel should be knowledgeable of the product  Usually occurs after the risk assessment
and the process
 QRM should be based on knowledge of the product  During risk control activities the following key
or processes concerned, according to the stage of questions should be asked: (KEY QUESTIONS)
the product life-cycle. (proactively & ■ What can be done to reduce or eliminate risks?
retrospectively) ■ What is the appropriate balance between benefits,
risks and resources?
2. Risk Assessment ■ Are new risks introduced as a result of the identified
 A systematic process of organizing information to risks being controlled?
support a risk decision to be made within a risk
management process. Risk control can include:
 When risk assessment is conducted, safety, and ■ not proceeding with the risky activity;
efficacy need to be considered in addition to the ■ taking the risk;
quality concerns. ■ removing the risk source;
QUALITY
■ changing the likelihood of the risk;
■ changing the consequences of the risk;
SAFETY
■ sharing the risk with another party (e.g. contractor);
EFFICACY
■ retaining the risk by informed decision.
 During the assessment all the risks that may Summary:
Risk control activities usually involve identifying controls and
reasonably be expected to occur when conducting
measures which may reduce or control the risk associated
the activity under evaluation should be listed.
with a failure mode or negative event.
 In the risk assessment the following basic
questions should be addressed: 4. Risk Review
■ What might go wrong?  Review or monitoring of output or results of the risk
■ What is the nature of possible risks? management process considering (if appropriate)
■ What is the probability of their occurrence and new knowledge and experience about the risk.
how easy is it to detect them?  Appropriate systems should be in place to ensure
■ What are the consequences (the severity)? that the output of the QRM process is periodically
monitored and reviewed, as appropriate, to assess
 Normally, potential risks in relation to the new information that may impact on the original
following should be considered: QRM decision.
■ materials and ingredients;  All records and documents associated with risk
■ physical characteristics and composition of the review should be signed and dated by the
product; person(s) carrying out the review and by a
■ processing procedures; responsible official(s) of the quality unit of the
company (quality assurance)

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5. Risk management tool CONTAMINATION AND CROSS-CONTAMINATION

 A variety of tools can be used for the purposes of PREVENTION IN PHARMACEUTICAL INDUSTRY
QRM, either alone or in combination. It is Contamination
important to note that no single tool or  is the undesired introduction of impurities (of a
combination of tools is applicable to every chemical or microbiological nature) or of foreign
situation in which a QRM procedure is used matter, into or onto a starting material or
intermediate or API during :

1. PRODUCTION
2. SAMPLING
3. PACKAGING OR REPACKING
4. STORAGE OR TRANSPORT

Cross-contamination
 is the contamination of a starting material,
intermediate or finished product with another
starting material or product.
 Manufacturers must have processes in place, to
not only avoid contamination scenarios but also
provide documented evidence that contamination
has not occurred.
 The reasons for contamination and cross-
contamination can vary and be caused by
technical or deficiencies within the organization
(personnel). The common sources of
contamination are identified in Figure 1 below.

PREVENTIVE MEASURES

 DESIGN OPPORTUNITIES
 EFFECTIVE AIRFLOW/EXTRACTION AND HVAC
DESIGN
 PERSONAL AND PROCEDURES
 CLEANING PROCEDURES

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2. If a Recirculation System is installed, the ratio of

1. DESIGN OPPORTUNITIES fresh air to recirculated air must be justified.
(EX. CENTRIO -AIRFLOW SYSTEM)
AREA OF PREVENTIVE MEASURES 3. Where possible, ventilation dampers and filters
DESIGN should be designed and positioned to be
 be of suitable size, construction and accessible from outside the manufacturing areas
location to facilitate suitable for ease of maintenance.
cleaning, maintenance and
4. Directional airflow within production or primary
appropriate operation (easy
transport & no traffic) packing areas assist in preventing contamination.
 have adequate space for placement
of equipment as well as production Note: Aside from the HVAC system, pharmaceutical
and packaging materials industry also uses AIR HANDLING UNITS that conditions the
 consider the sequence of operation air.
during the design phase; paying
FACILITY particular attention to the location of • Important equipment for HVAC:
equipment and removal of 1) UNIDIRECTIONAL AIRFLOW (UDAF)
unnecessary traffic
 A rectified airflow over the entire cross-sectional
 have adequate internal
temperature, ventilation and
area of a clean zone with a steady velocity and
lighting; approximately parallel streamlines.
 have smooth surfaces (no cracks, 2) LAMINAR AIRFLOW (LAF)
crevices or shedding), which are  A rectified airflow over the entire cross-sectional
easily cleaned area of a clean zone with a steady velocity and
 have adequate segregation of approximately parallel streamlines (modern
materials products and components standards no longer refer to laminar flow but have
to further reduce the risk of cross adopted the term unidirectional airflow).
contamination
3) HIGH EFFICIENCY PARTICULATE AIR FILTER
 This type of air filter can theoretically remove at
 All equipment should have smooth least 99.97% of dust, pollen, mold, bacteria, and
inert surfaces which are not additive any airborne particles with a size of 0.3 microns
or adsorptive, and installed in an (µm).
EQUIPMENT area that is easily cleaned 4) AIR-LOCKS
Ex. Stainless steel SSG-310 (most inert
 An enclosed space with two or more doors, which
type of stainless steel in an equipment)
is interposed between two or more rooms.
 if the equipment is difficult to clean,
then consider using it for a dedicated  Ex. Dispensing area (an airlock room; one way)
purpose.
HVAC  Airborne contaminants are
SYSTEM controlled through effective
(HEATING, ventilation and filtration.
VENTILATION,
AIR-  The criteria is detailed in the next
CONDITIONING section, Effective Airflow/Extraction
SYSTEM) and HVAC Design.
 The best way to prevent viruses and
other contamination is through
HVAC filter.

2. EFFECTIVE AIRFLOW/ EXTRACTION AND HVAC 5) PRESSURE CASCADE

DESIGN  A process whereby air flows from one area, which
is maintained at a higher pressure, to another area
 External contaminants should be removed by at a lower pressure
effective filtration of the supply air, to retain the Note: AIR-LOCKS + PRESSURE CASCADE = will confine
required cleanroom classification. potential airborne contaminants within a specified area

 Internal contaminants should be controlled by

displacing the airflow:

1. The Pressure Differentials should be of sufficient

magnitude to ensure containment and prevention
of flow reversal without creating turbulence.

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UTILIZE a closed manufacturing system.

Example of HVAC DESIGN: This is where the product is not
(unidirectional airflow/ventilation) exposed to the immediate room
environment (and vice versa).
PERFORM an area line clearance according to
approved procedures following
each cleaning process and
between each batch/campaign.
ZONE the facility
USE Use Cleaning Status labelling on all
equipment and materials used
within the manufacturing facility.

4. PERSONNEL TRAINING AND CLOTHING

 Prior to and during employment, all personnel
should undergo the relevant GMP and cleaning
training, and be periodically assessed for
competency.
 The importance of gowning should be implicit and
competency of gowning/de-gowning procedures
should be clearly documented and routinely
monitored particularly in sterile situations via
Additional info only: microbiological testing.
 Air duct dampers are  Personnel should wear appropriate clothing to the
also commonly known duties they perform and the environment they
as HVAC dampers and work in. These include:
duct dampers. These
duct dampers are 1. Personnel protective equipment (PPE)
movable plates that you 2. Clean body coverings (refer to Figure 3: Basic
place in the ductwork. GMP Gowning)
An air duct damper 3. Cleanroom clothing (appropriate for each
allows you to perform cleanroom classification), which can
two main jobs: Cut off the central air conditioning withstand repeated wear and laundering with
to any unoccupied rooms. Regulate temperature minimal deterioration (refer to Figure 4:
room-by-room. Cleanroom Gowning)
Notes: 4. Appropriate footwear (e.g.: steel-capped
1. Any disruption to unidirectional flow must be quickly shoes and shoe covers), which is provided by
restored and the contamination around the obstacles the company.
adequately diluted.
2. The air volumes supplied to laminar flow rooms are a lot
greater than those supplied to a conventionally ventilated
room; they are therefore much more expensive to operate.
3. PERSONAL AND PROCEDURES
(MANUFACTURING PROCESS)
 There are many opportunities for contamination of
raw material, intermediates or packaging
materials throughout the manufacturing process.
 To minimize risk of contamination and cross-
contamination, the following should be
considered:

DEDICATE the facility to the manufacture of a

single formulation of product.
MANUFACTURE products in a campaign, with the
appropriately qualified cleaning
processes and checks performed
in-between batches to minimize
the amount of product
changeovers.

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 If cleaning procedures are still in development,

the equipment must be cleaned until the
residual levels or product and cleaning agents
meet the acceptance criteria, before
commencing manufacture of a subsequent
batch
 Document the cleaning status of each
equipment in logbooks
GENERAL HOUSEKEEPING
 Cleaning and housekeeping of all areas within a
facility should be performed routinely. This
includes floors, ceilings, walls, work surfaces:
 Empty bins regularly
 Clean any spills immediately
 Remove all unnecessary equipment and store
appropriately

Conclusion
 It is critical that the facility, equipment and HVAC
design allows for effective cleaning and ensures
cross-contamination is controlled.
 The facility and equipment should:
 be appropriately installed and qualified
 have effective cleaning procedures validated.
 have procedures documented in such a way as to
5. CLEANING PROCEDURES
ensure that each operator consistently performs
 Having inappropriate or ineffective cleaning
the task, leaving no room for interpretation.
procedures could invariably cause cross-
GOOD DOCUMENTATION PRACTICE (GDocP)
contamination between batches and/or
 Aka Good recordkeeping
campaigns.
 It constitutes an essential part of the quality
 To minimize the risk of contamination and cross-
assurance system and is key to operating in
contamination, cleaning procedures must:
compliance with GMP requirements.
1. Be appropriately designed, taking into
 Documentation may exist in a variety of forms,
consideration the product formulation, the
including paper-based, electronic or photographic
equipment design and functionality of the
media.
system
 “it it’s not documented, it didn’t happen”
2. Clearly documented and not be open to
interpretation TERMINOLOGIES
3. Be validated to provide documented evidence  DOCUMENT
that the procedure utilized is capable of  An approved instruction either in paper or
cleaning the equipment to the predetermined electronic form which guides about how an activity
acceptance criteria. shall be executed.
 After cleaning, calibration of the equipment and  RECORDS
validation of the procedure is done in a  Provide evidence that activities have been
documented manner. performed or results have achieved
 The following lists some of the cleaning criteria for  Often considered as document
cleaning equipment and general housekeeping. OBJECTIVES
 The main objective of the system of
CLEANING EQUIPMENT documentation utilized must be to establish,
 Labels should be attached to each piece of control, monitor and record all activities which
equipment to clearly state the cleaning status directly or indirectly impact on all aspects of the
 Ensure that operators are trained in the quality of medicinal products.
relevant cleaning procedures  There are two primary types of documentation
 Ensure that utilities and services (such as used to manage and record GMP compliance:
steam and water) have been tested and instructions (directions, requirements) and
monitored routinely for any microbial growth records/reports. Appropriate good documentation
and cleanliness of supply practice should be applied with respect to the type
 Do not use cleaning aids such as bristles, of document.
brushes and particle-shedding clothes for
manual cleaning of equipment

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 The term ‘written’ means recorded, or instructions. Inprocess controls and process
documented on media from which data may be analytical technologies to be employed should be
rendered in a human readable form. specified where relevant, together with
PURPOSE OF DOCUMENTATIONS acceptance criteria.
1. Defines specifications and procedures for all  Procedures: (Otherwise known as Standard
materials and methods of manufacture and Operating Procedures, or SOPs), give directions for
control performing certain operations.
2. Ensures all personnel know what to do and  Protocols: Give instructions for performing and
when to do it recording certain discreet operations.
3. Ensure that authorized persons have all  Technical Agreements: Are agreed between
information necessary for release of product contract givers and acceptors for outsourced
4. Ensures documented evidence, traceability, activities.
provide records and audit trail for  Ex: Contracts, Employee’s contract, Toll
investigation manufacturer/supplier contract
5. Ensures availability of data for validation, (under GDP, cGMP, GDocP)
review and statistical analysis 2. Record/Report type:
SUITABLE CONTROLS SHOULD BE  Records: Provide evidence of various actions
IMPLEMENTED TO ENSURE THAT: taken to demonstrate compliance with
instructions, e.g. activities, events, investigations,
DATA ACCURACY  Recorded accurately; and in the case of manufactured batches a history
 Cross-checked for errors of each batch of product, including its distribution.
(IS IT TRUE?)  Not intentionally misleading Records include the raw data which is used to
 Genuine, true data generate other records. For electronic records
DATA INTEGRITY/  Validated; regulated users should define which data are to be
VALIDATION  Relevant to the reporting used as raw data. At least, all data on which
REPORTING requirement quality decisions are based should be defined as
 Not changeable after original
raw data
(IS IT VALID?) record-keeping entry ; Should
be protected and backed-up
 Certificates of Analysis: Provide a summary of
REPORTING/  Information is recorded testing results on samples of products or
RECORD-KEEPING contemporaneously; materials1 together with the evaluation for
TIMELINESS  Real-time record keeping compliance to a stated specification.
including date stamps  Reports: Document the conduct of particular
(IS IT TIMELY?)  Data stamps – Automated exercises, projects or investigations, together with
time stamping prevent results, conclusions and recommendations.
memory issues or prevents
editing of original data;
Documented at the time
activity is done
LEGIBILITY  Clarity;
 Legible
(IS IT READABLE  Readily accessible
BY THE OTHER
PERSON?)
IDENTIFIABLE  Clear records that can identify
(TRACEABLE) the person who actually
records the data
 Who documented, when and
how; Must be enduring, long-
lasting

REQUIRED GMP DOCUMENTATION (BY TYPE)

1. Instructions (directions, or requirements) type:

 Specifications Describe in detail the requirements
with which the products or materials used or
obtained during manufacture have to conform.
They serve as a basis for quality evaluation.
 Manufacturing Formulae, Processing, Packaging
and Testing Instructions: Provide detail all the
starting materials, equipment and computerized
systems (if any) to be used and specify all
processing, packaging, sampling and testing

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CATEGORIES OF DOCUMENTATION 4. NEVER sign your name for work performed by someone
1. Primary records else.
 such as those obtained from the master formula, 5. Limit the use of abbreviations and acronyms.
manufacturing and packaging instructions. 6. Ball point non-water-soluble pens of blue or black colored
2. Supporting procedures inks are employed to make entries.
 such as instructions on how to perform a 7. Do not leave blank spaces (put N/A if it does not contain
manufacturing step or test methodology. information)
3. Subsidiary records 8. Never use line with or w/o arrows to show continuation of
 which support the process as it is being carried values or entries.
out, such as environmental monitoring or 9. Corrections to written records must be made properly
preventive maintenance/calibration on process or
lab equipment. ERROR DESCRIPTIONS
4. Quality control records 1. Calculation error
 include all lab testing results for the process or 2. Transposition
products and al investigative reports and records. 3. Illegible entry
PRINCIPLES OF GOOD DOCUMENTATION PRACTICES 4. Wrong entry
1. A document with original signatures should  Don't remove any pages or portions from a note
never be destroyed. book
2. Never falsify information  Don't make any temporary entries in a bit of
3. Never do white-out and cover-over-tapes paper of hand Preserve the notebooks intact.
4. Never obliterate information or record  Do Not Use "Sticky" Notes.
5. Never over-write a record  Do Not Back-Date or Post-Date.
6. Never use pencil, use permanent ink in writing  Do Not Use Asterisks That May Cause Confusion
7. No spaces, lines or fields are to be left blank. (Such as Using the Same Asterisk for Different
8. Never use symbols (Ditto or arrow) Footnotes).
BENEFITS OF GOOD DOCUMENTATION PRACTICES  Do Not Transcribe Data.
 Avoid Use of Unbound Laboratory Notebooks
1. Compliance to regulatory requirement
2. Build confidence on system and practices
3. Correct, complete, current and consistent information
4. Effectively meets customers and stakeholders'
requirements
5. Ensure the traceability
6. Useful for review, investigation & CAPA (corrective &
preventive actions)
7. Solve complicated problems
NOTE:
8. Reduce or eliminate assumptions and second- guessing
In data writing – avoid sloppy writing, write legibly.
9. Eliminate the need to re-ask the same questions
3 persons must validate, review, checked
10. Specify clear instructions
(PART OF GLP & GDocP)
11. Consistent quality, yield and performance.
WHY DO PEOPLE SOMETIMES FAIL TO DOCUMENT
LAB RECORD WITNESSED/CHECKED/
EVENTS/ACTIVITIES PROPERLY? REVIEWED BY
 Busy -Enter enough details so - The second check: When
 Distractions the document can be one person performs the
 Lack of knowledge about GDocP understood in the future. task and the second
 Don’t clearly understand what or when to -Documents should be person verifies that it has
document signed and dated by the been performed correctly.
 Procedure may not be completely understood or person who performed the - Double checking our
followed test. work provides additional
 People aren’t always held accountable -A reference to the assurance that no
 People will make mistakes (not perfect) identification of the sample mistakes were made.
 Don’t always make corrections properly analyzed should be - The person who is the
 Do not relate records to auditing included. "verifier" must be clear as
 Do not understand the legal role of documentation to what they are verifying
RECORD WRITING (DATA ENTRY) by affixing their signature
1. Enter completely & accurately the information at the time to the document.
work is performed.
2. Affix signature or initials (according to procedure)
3. When one or more person completes the task, all person
must sign the document

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TRANSFER OF TECHNOLOGY FACTS OF TECHNOLOGY TRANSFER

 This topic in pharmaceutical industry place a vital  Government laboratories to private sector firms
role in the process of drug discovery to product  This type of technology transfer is advantageous
development and to the full-scale because the government labs can get good
commercialization. FUNDING/FINANCIAL SUPPORT.
 Technology transfer is the practice of transferring  Between private sector firms of same & of
scientific findings from one organization to another different countries
for further development and can become  This type of technology transfer occurs due to the
available to the public. lack of appropriate financial resources or
 It is very important to elucidate all the necessary inadequate knowledge of regulatory
information for technology transfer from the R&D requirements.
DEPARTMENT TO PROCESS AND DEVELOPMENT  The private sector that develop the technology is
LABORATORY. paid by the another sector that absorbs the
 Technology transfer is both integral and critical to technology (LICENSING IN/OUT)
the drug discovery and development process for  From academia to private sector firms
new medicinal product.  when a private company offers the student
 It is helpful to develop dosage forms in various researchers to fulfill the research into reality.
ways like it provides efficiency in process, helps to  Advantage: Money can be saved
maintain quality of product, helps to achieve  Academia, government, and industry
standardized process, which in turn facilitates collaborations
timely & cost-effective production.  The government will provide the necessary funds
ACCORDING TO: WHO to the academe institution in developing
 Transfer of technology is defined as “a logical technology that can be transferred to the industry
procedure that controls the transfer of any process IMPORTANCE OF TECHNOLOGY TRANSFER
together with its documentation and professional  To elucidate necessary information to transfer
expertise between development and manufacture technology from R&D to actual manufacturing by
or between manufacture sites”. sorting out various information obtained during
 It is the process by which an original innovator of R&D.
technology makes its technology available to  Demonstration of necessary information to
commercial partner that will exploit the technology transfer from research and
technology development to actual manufacturing.
IN THE PHARMACEUTICAL INDUSTRY:  To elucidate necessary information to transfer
 Processes of successful progress from drug technology of existing products between various
discovery to product development, clinical trials manufacturing places.
and ultimately to full-scale commercialization.  To exemplify specific procedures and points of
concern for smooth technology transfer. For the
STANDARDS IN THE DEFINITION OF TECHNOLOGY smooth manufacturing of commercialized
1. Knowledge must be systematic. products.
 It must be organized in terms of providing solution  The technology transfer shows importance in
to the problems. extended benefits of the research and
2. Knowledge must exist in certain places development to the society.
 Either knowledge in someone’s mind or in FLOW CHART OF TECHNOLOGY TRANSFER IN THE
document PHARMACEUTICAL INDUSTRY:
 Must able to be presented from one person to In pharmaceutical industry:
another  Designing a dosage form needs scale up
3. Must have purpose-orientation. production at several stages
 can be utilized for useful purposes in industry and
commercial field.
 Must have a goal which is to be MARKETED AND
COMMERCIALIZED.

METHODS FOR TECHNOLOGY TRANSFER

1. LICENSING OUT
- company right is given to another party.
2. LICENSING IN
- small companies and lack facilities to do basic research
and these facilities want to buy other research.
NOTE:
Licensing is the most common way/method of technology
transfer.

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 Scale-up 1. RESEARCH PHASE (DEVELOPMENT OF

- Around 100-1000 production just for the quality TECHNOLOGY BY R&D):
control and stability testing
 Production batches a. Design of procedure and selection of excipients
- Much larger production of products after the by the R&D
process validation  A completely different testing and compatibility
REASON FOR TECHNOLOGY TRANSFER studies conducted for the procedure and
1. Due to lack of manufacturing capacity excipients
- The developer of the technology may only have b. Identification of specifications and quality by the
manufacturing equipment that is suitable for lab R&D
and small scale operations and must partner with  Generally, it is considered by the R& D department
another organization to do large scale that the quality of a product ought to meet the
manufacturing. specification of the innovator product.
2. Due to lack of marketing distribution and  Additional stability studies are carried out for
distribution capability innovator product before creating the document
- the developer of technology may have fully (manufacturing order/schedule) for mass
developed the technology and even obtained production.
regulatory approvals and product registrations,
but it may not have the marketing and distribution 2. DEVELOPMENT PHASE (TECHNOLOGY
channels and must collaborate with another TRANSFER FROM R & D TO PRODUCTION)
organization that has the capability. - R&D provides technology transfer dossier (TTD)
3. Due to lack of resources to launch product document to product development laboratory,
commercially which contains all the information of formulation
- The original inventor of technology may only have and drug product as follows.
resources to conduct early-stage research and a. Master formula card (MFC)
phase I and phase II clinical trials. - It includes product name along with its strength,
4. Forming alliances with partners that can generic name, MFC number, page number,
progress the development of the technology to effective date, shelf life and market.
take it to market. b. Master packaging card
- The developer of the technology might have the - Gives information about the packaging type,
resources to take the technology to a particular material used for packaging, stability profile and
state of development form animal testing to shelf-life of packaging.
toxicology studies but has no resources to take the c. Master Formula
study into clinical and regulatory phases. - Formulation order and Manufacturing Instructions
- Only involves pre-clinical trial Master formula gives idea of process order,
5. Forming alliances with partners with environment conditions required and
manufacturing capability manufacturing instructions for dosage form
- Same with reason no.2 development
6. Forming alliances with partners with marketing d. Specifications and Standard Test Procedures
and distribution capability. (STPs)
- No marketing channel - it helps to know active ingredients and excipients
7. Exploitation in a different field of application profile, in- process parameters and specifications,
- Each part may only have half of the solution product release specification and finished product
- The developer of the technology might have the details.
capability of exploiting the technology itself in the
field of diagnostic applications and may grant 3. PRODUCTION PHASE (OPTIMIZATION AND
exploitation rights to the commercial partner for PRODUCTION)
the exploitation of the therapeutic application.
STEPS IN TECHNOLOGY TRANSFER PROCESS a. Validation and Production studies
 Technology transfer is not a single/one-way - Production is implemented after validation studies
process. It involves a lot of people in order to have that can verify that process is able to stabilize the
a successful technology transfer. product based on transferred manufacturing
 During development of a formulation, it is formula.
important to understand the procedure of - Manufacturing department accepting technology
operations, critical or non-critical parameters of is responsible for validation and the R&D
each operation, production environment, department transferring technology should take
equipment and excipients availability should be responsibility for validation such as performance
taken into account during the early phases of qualification, cleaning and process validation.
development of formulation so that successful
scale up can be carried out.

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b. Scale up for production early development phase to final application of

- involves the transfer of technology during the approval.
small-scale development of the product and  Data for raw materials and components
processes. It is essential to consider the production  Rational for the dosage form and formula designs
environment and system during development of and design of manufacturing ways. modification in
process. histories of vital processes and control parameters
- It is essential to consider the production  Stability profile, specifications and test methods of
environment and system during development of drug substances, intermediates, drug products,
process. Operators should concentrate on keeping raw materials, and components, which also
their segment of the production running smoothly. include the validity of specification range of
TECHNOLOGY TRANSFER CORE TEAM important tests such as contents impurities and
1. Process technologist dissolution.
- Central focus for transfer activities.  Rational for selection of test methods, reagents
- Collates documentation from the donor site and columns verification of results.
- Performs initial assessment of the transferred 2. Technology Transfer Plan: describes the things
project for Feasibleness, Compatibility with site and contents of technology to be transferred and
capabilities and Establishes resource needs elaborate procedures of individual transfer and
2. QA representative transfer schedule, and to determine judgment
- Reviews documentation to work out compliance criteria for the completion of the transfer.
with marketing authorization (MA) 3. Report: Report completion of technology transfer
- Reviews analytical strategies with QC to work out is to be created once information is taken
capability, instrumentation training consequently to the plan and are evaluated to
requirements. substantiate that the planned judgment criteria
- Initiates conversion of donor site documentation are met.
into local systems or format. 4. Exhibit: After taking a scale-up batch of the
- Initiates or confirms regulatory needs, e.g., an product, manufacturing of exhibit batches take
amendment to manufacturing license; variations place. In case of exhibit, batch sizes are increased
to MA if method changes needed, etc. along with equipment, and their process is
3. Production representative involved. They are done for filing purposes in
- Reviews process instructions (with process different regulatory agencies.
technologist) to verify capacity and capability. - Not for mass production but for EXHIBIT only
- Considers any safety implications, e.g., solvents; NOTE:
toxic; sanitizing materials - In implementation of technology transfer, it is
- Considers the impact on local standard operating important to avoid technology transfer by only
procedures (SOPs). handing over the technology transfer
- Considers the training requirements of documentation.
supervisors or operators - It must be a shared responsibility even after
4. Engineering representative handing it over to the other personnel/
- Reviews (with production representative) - Continuously monitor the documentation
instrumentation requirement. SUCCESS OF TECHNOLOGY TRANSFER
- Initiates required engineering modifications, - In pharmaceutical trade, technology transfer
change or part purchase. suggests that action to transfer of data and
- Reviews preventative maintenance and technologies necessary to realize quality of
calibration impact, e.g., use of a lot of aggressive design of drugs throughout manufacturing. The
ingredients, more temperature sensitive method, technology transfer does not mean one-time
and modifies consequently. actions taken by the transferring party toward the
5. QC representative transferred party however, suggest that
- Reviews analytical requirement. continuous information exchange between both
- Availability with instruments. the parties to maintain the product
- Responsible for analytical technique transfer for manufacturing. Technology transfer is a complex
drug substance and drug product. issue and should be deal with using holistic
TECHNOLOGY TRANSFER DOCUMENTATION approach
1. Development Report: - INVOLVES 5Cs
- It is used at the pre-approval examination as a
valid document for quality design of new drug. The
ultimate goal for a successful technology transfer
is to possess documented evidence.
 Data of pharmaceutical development of new drug
substances and drug products at stages from the

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1. Communication  In large scale operations, mechanical means of

- Must involve good and effective two-way handling these materials are often necessary.
communication  Lengthy transfer lines may result in material loss
- Removes barrier between person by person or which affects the weighing accuracy.
organization by organization  *If hand scooping: Challenge – dust control, it is
2. Certainty better to use vacuum system in weighing to control
- Lack of certainty and consequential high level of dust
risk both real and perceived are recognized as the  The type of dispensing system selected depends
major impediment to a successful establishment on the characteristic of the materials: density
and ongoing operations of the functional market. and static charge of ingredients
3. Challenges  Any material handling must deliver accurate
- May be in the form of restrictions from linkages or amount of ingredient to the intended destination
organizations
- Different area of expertise/practice METHODS:
- Misunderstanding 1. Hand Scooping and Weighing
- Documentation errors (not following GDocP) - Done in the laboratory
4. Capacity 2. Material lifting assistance
- Enhancing the transfer of technology that supports  Vacuum transfer
sustainable development and largely about  Bag lifters In large
creating favorable circumstances for technology 3. Automated dispensaries
scale
transfer ensuring that stakeholders have the  Vacuum loading system
operations
ability to fulfil the roles and make the  Screw feed systems
responsibility.  Metered pump
5. Commitment
- There may be a good commitment to overcome
the challenges. Providing technology users with CHALENGES ENCOUNTERED:
choice, deserve and desire. 1. Weighing accuracy
- Committed to produce a quality product To counteract or overcome the challenge:
MANUFACTURING OF SOLID DOSAGE FORMS  Reduce the reduce the transferring of
 Tablets, Capsules, Powders, Granules ingredients from one place to another
 In scaling up the manufacture of the solid dosage  Slowly transfer the ingredients from one
forms, from experimental laboratory, batch size container to another to reduce the
to intermediate and large-scale production each dropping height of the material
stage of the operation must be carefully 2. Dust control
considered. The scale up may involve major - Occurs since majorly dealing with
process and process change that utilizes powders/powdered materials, so the dust control
technique and equipment that is either unsuitable is a challenge
or unavailable on the laboratory scale. To counteract or overcome the challenge:
 Using vacuums
Processes/ Operation Involved on Solid dosage Forms  Proper ventilation in the dispensing
(performed in laboratory) area to control the dust
3. Lot control of each ingredient
Weighing
Trituration,
Levigation,
Incorporation,
Mixing,
Tableting - Since they are numbered and sometimes has the
Process/Punch
Spatulation Blending Method same color, it may be prone to errors in
identification or mismatch.
To counteract or overcome the challenge:
SCALE UP PRODUCTION OF SOLID DOSAGE FORM  Proper LABELING/LABEL is a must in
(large-scale production) order to properly identify and prevent
1. Dispensing cross-contamination
2. Milling 4. Material movement
3. Mixing - The dispensing area must be spacious for easy
4. Granulation access and movement of the equipment/materials
5. Tableting (avoid traffic) since they are bulky and heavy.
6. Coating - Using of carts for moving materials
7. Encapsulation Note: One cart per material (avoid cross-
[Link] (in manufacturing) contamination and prevents confusion for the person
 Defined as “act of measuring or weighing of raw conducting the dispensing process
materials or ingredients.”
 In the laboratory: Materials are simply scooped,
dumped or poured by hand.

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[Link] enclosed within a rigid metal case, which swing out

- Mechanical process of reducing the particle size of radially from the rotating shaft.
solids.  Vibration Mill. Filled to approximately 80% of the
- Few materials used in pharmaceutical exist in total volume with porcelain or steel balls and then
optimum size and most materials must be the whole mill is vibrated
comminuted at some stage during the production 4. Attrition
of dosage form. (the smaller particles size the - Principle: Breaking down of materials by rubbing
better especially for tablets and capsules; easy action (pressure) between two surfaces.
compression & encapsulation) - Type:
- Sizing, size reduction, grinding, crushing,  Roller Mill – two cylindrical rolls, mounted
pulverization have been used synonymously with horizontally and rotated about their long axes.
comminution depending on the product, (usually in rice mills)
equipment and process. 5. Combined impact and attrition
Note: Sizing, size reduction, grinding, crushing, - 200 mesh
pulverization is SAME with Milling/ comminution - The name of the mill depends on the material used
in reducing the particle size
Importance: (in pharmaceutical industry) - Combination of impact and attrition
1. Increase specific surface of the substance (The - Particular useful when sticky materials are grinded
smaller the particles size, the greater the surface  Ball Mill – partially filled with balls of steel or
area which enhances the dissolution or solubility of pebbles which act as the grinding medium
the drug particles.)  Pebble mill – pebbles
2. Increase the free surface energy of milled  Rod mills – rods/bars; particular useful when
substance. sticky materials is grinded
3. Significantly increase the speed of substance and [Link]/BLENDING
diffusion process - Defined as a process that tends to result in a
MILLING ACTION: randomization of dissimilar particles within a
1. Cutting (shearing) system. Process of putting together ingredients in
- 20-80 mesh one mass to obtain uniform dosage units.
- Equipment: - Powders to be used for encapsulation or to be
Rotary cutting mill granulated prior to tableting or encapsulating
 uses sets of knives (2-12 rotating knives) must be well blended to ensure good drug
in reducing the particle size. Used for distribution.
tough and fibrous materials such as - Inadequate blending results to drug content
vegetables and crude drugs but not for uniformity variation.
friable material - Mixing of powder is the key step in the
2. Compression manufacturing of solid dosage forms.
- Powder size: 20-200 mesh (finer than cutting) - Small Scale Preparation – spatulation, trituration,
- Principle: geometric dilution
 Size reduction is done by crushing due to TYPES:
heavy weight of steel pestle. (large-scale 1. BATCH MIXING
basis)  larger size of mortar and 2. CONTINUOS MIXING
pestle BATCH MIXING CONTINUOUS MIXING
 End – runner mill and Edge-runner mill
are used for fine grinding of abrasive • All ingredients are loaded •Single high-volume
materials but not for soft materials. into the mixer together or product loading in
- Types: in a pre-defined sequence accordance with the
1. End – runner mill: weighed pestle is turned by a until homogenous mixture formulation.
friction of materials passing beneath it as the is achieved. • There is uninterrupted
mortar rotates under powder. • When materials to be supply of freshly mixed
2. Edge – runner mill – pestle equivalent muller mixed is limited in volume. materials and is often
mounted horizontally and rotating against a bed • Mixed in kilogram/batch. desirable when large
of powders • Equipment: volumes of materials are
3. Impact 1. Twin – shell (V-shell) to be handled.
- Powder size: 4-325 mesh blender Employed in
- It uses hammer or bars; also used in almost all dry-dry or dry-wet
drug materials except abrasive materials. (liquid) material.
- Types:
 Hammer Mills. Consists of a series of 4 or more
hammers, hinged on a central shaft which is

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• Loading is kilogram/hour Sizing again with a mesh of 12-20. Addition of

lubricant. Blending. Encapsulation
 DISADVANTAGES:
1. Labor intensive. (Employs wetting and drying steps)
2. Time Consuming. more binding agents that will be
added or liquids the drying is time consuming.)
2. Double cone blender 3. Not applicable for moisture sensitive and heat labile
3. Sigma blender drugs.
4. GRANULATION
 Generic description for a process of particle
enlargement in which particles are agglomerated
while retaining the integrity of the original
particles. A process of granule formation for
flowability and compressibility.
 It is the most widely used technique to prepare
powders for compaction or compression.
 The reason of granulation (increasing particle
size) are as follows:
 To impart good flow properties to the
materials. (So that the tablet presses and
encapsulators can be properly feed.
Uniform tablet and capsule weight are
maintained)
 To increase the apparent density of the
powder. Note:
 To change the particle size (So that the Preparing a damp mass- (consideration) In dealing
binding properties on the compaction with liquid binders, care must be observed in using
can be improved) binders because it may affect the dosage form.
 In granulation, there are 2 types of granules  Overwetting of the powder (too much liquid
produced via granulation: binder) may result to TOO HARD GRANULES
1. Good granules – pass through sieve # 20 but  Underwetting of the powder may result to
not # 40 TOO SOFT GRANULES
2. Fine Granules. pass through sieve # 40,
commonly employed to fill interparticulate DRY GRANULATION
spaces with a limit not more than 10%  These methods are useful for materials that are
METHODS: sensitive to heat and moisture, but which may not
1. WET GRANULATION be suitable for direct compression. (aspirin and
2. DRY GRANULATION multivitamins: moisture sensitive)
3. DIRECT COMPRESSION  DOES NOT USE LIQUID BINDERS BUT INSTEAD USES
4. FLUID BED PROCESSING (A SUBTYPE OF WET HIGH PRESSURE TO FORM THE GRANULES
GRANULATION)  Dry granulation involves the aggregation of
particles by high pressure to form bonds between
COMMON REASONS FOR GRANULATION: particles by virtue of their proximity. This process
 To impart good flow properties to the materials eliminates the wetting and drying step.
 To increase the apparent density of the powders  Two approaches to dry granulation
 To change the particle size distribution 1. SLUGGING. In this method the powdered mixture
WET GRANULATION is slugged or compressed into large flat tablets
 These methods involve the addition of liquid (slug) or pellets about 1-inch diameter, which then
(alcohol or water) and usually, a polymeric binder be subsequently broken down into granules via
is added to the powder starting material, in the oscillator granulator.
form of agitation to promote agglomeration 2. ROLLER COMPACTION. Instead of slugging,
followed by a drying process. powder compactor may be used to increase the
 PRODUCES MOST ELEGANT TABLET density of a powder by pressing it between rollers
 Most commonly used in tablet manufacturing at 1-6 tons forming sheets via chilsonator. Power is
because it produces a good tablet. feed between two rollers rotating in opposite
 Reduce particle size by grinding. Blending and direction. Rollers can be flat which can produce a
mixing of Vshell blender. Adding adjuvants and sheet of compacted materials. Often preferred
excipients. Adding the binders to make granules. than slugging.
Screening with a mesh of 6-8. Drying with oven.

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FLUID BED PROCESSING

 Particles are placed on conical piece of equipment
and are vigorously dispersed and suspend while
the liquid excipient is sprayed on the particles and
the product is dried, forming granules or pellets of
defined size. All in one granulation process.
 3 types: Top spray, Bottom spray and Tangential
spray
 Advantages:
 Improves flowability and compressibility.
 Suitable for drugs with poor properties.
 Uniform weight and content.
 Less dusty.
 Uniform distribution of color.

 Advantages: Less equipment used & Less timed

consumed since it eliminates the WETTING AND
DRYING PROCESS compared to wet granulation
 Disadvantages: Uneven distribution of colors
(mottling) & Dusty granules

DIRECT COMPRESSION
 Intended for powder or granular chemical that
possess free-flowing and cohesive properties that
enables them to be compressed directly in a tablet
machine without any need of granulation.
 Most commonly employed diluent:
microcrystalline cellulose and anhydrous lactose

 Example: Potassium chloride, Sodium chloride,

Sodium bromide

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5. Tableting 4. Lubricity
 Tablets are primarily preparing via compression - Although not all are required to have lubricity
method. Tablet pressers can be single activity, one of the ingredients in the tablet
punch/eccentric presses or Multi-station/rotary formulation must act as a lubricant. (to reduce
presses. friction)
Single press 5. Appearance
 can produce 200 tablets/minute - The tablet must be elegant in its appearance.
 In the laboratory, the amount of tablet - The ingredients must provide elegance to the finish
being produce will depend on the person product.
operating the machine. (manually) - The colorants and shape of the tablet must be
Multi-station/rotary press elegant and free from defects.
 Can produce 10,000 tablets/minute - When pressed, it must not form mottling/ picking
 Commercial production is performed in rotary of the edges of the tablet.
presses tablet machine due to their high output. 6. Disintegration
- Materials of the tablet formulation must
Tablet Machine: disintegrate and dissolve appropriately. It must be
1. Hopper – contains the granules or powders for tableting dissolved within the desired time because
2. Feed shoe (feed frame) – transfers the materials from the disintegration and dissolution are important
hopper to the die activity processes for a drug to produce its activity.
3. Die Cavity - responsible for the size and shape of the 7. Dissolution
tablet - Flowability and Compatibility - the most important
4. Cams- guide the movement of the punches of them all.
5. Punches •- compaction of the tablets, determines the TABLET EXCIPIENTS
hardness of the tablet - ensure that the tableting operation can run
satisfactorily and the tablets of specified
TABLET FORMULATION quantity/quality are prepared so depending on the
- We have to keep in mind that a tablet must intended main function.
possess the specific properties to optimize
technical feasibility, stability and bioavailability of ESSENTIALS NON-ESSENTIALS
the formulation. -they build majority of the -considered as the
Requirements for Materials Used in Tableting tablet miscellaneous /extra
1. Compatibility of drug substances with excipients -tablets will not be form ingredients
- The excipients must be compatible with the active without them -tablets provide its
ingredients -Example: diluent, expected function without
2. Flowability binders, disintegrants, them.
- The formulation should have sufficient flowability flow activators Ex: colorants, flavorants
to ensure that the appropriate quantity of powder ESSENTIAL TABLET EXCIPIENTS
flows into the dyes of the tablet machine on the DILUENT (FILLERS) (BULKING AGENTS)
consistent bases. - Added to increase tablet size which is practical for
- Powder must flow properly from the hopper to the compression and suitable for handling.
die for uniform content and weight of the tablet. - Normally, the tablet should way at least 50 mg to
be compressed. (in lower limit in terms of powder
PROBLEMS ENCOUNTERED WHEN FLOWABILITY IS NOT volume and weight required to be compressed)
GOOD IN THE FORMULATION: - It must:
1. ARCHING OR BRIDGING 1. Inert & non-hygroscopic
- Granules separate at the neck of the hopper and - Diluents added must be chemically inert (not
flow stops completely. (supplemental info) causing any reaction with the active ingredients
2. RAT HOLING and other excipients)
- In this case, particles segregate near the wall of the - Non-hygroscopic (must not absorb moisture from
hopper and at the center flows continues forming the environment)
hole. In rat holing, flow rate decreases. 2. Biocompatible
- They do not interact/interfere with the processes or
Note: when these two problems are encountered, there is activities in our body.
an erratic flow of the powder or no flow of the powder at all. - Does not interfere with the metabolism of the drug
3. Compactibility (compressibility) 3. Possess good biopharmaceutical & technical
- The aim of the formulator is to design a properties
formulation that will reliably compact to form a - Diluents should be water-soluble or hydrophilic
strong tablet thus a drug material should have a (biopharmaceutical property)
good compressibility property. - Diluents should be compactible/compressible and
must have a dilution property /can be diluted with

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addition of another component. (technical BINDERS (ADHESIVES/BINDING AGENTS)

property) - Substances used to cause adhesion of powder
4. Have an acceptable taste particles in tablet granulations
5. Cheap - Agents that imparts cohesiveness to powder
- Cost of the diluents moisture and they also provide mechanical
COMMONLY EMPLOYED DILUENTS: strength to the tablet
(FILLERS/BULKING AGENTS)
Lactose BINDERS CAN BE ADDED INTO POWDER IN DIFFERENT
- most common filler in tablets WAYS:
- Because it possesses a good filler property so it 1. Binders can be added into the powder as a dry
meets the requirements under diluents like lactose powder mixed with the other ingredients before
dissolves readily in water to have a pleasant wet granulation. During granulation/
taste. agglomeration, the binder might dissolve partly or
- Has a pleasant taste since it is a sugar completely in the agglomeration liquid. (internal
- It is non-hygroscopic and fairly non-reactive. binders)
- It shoes good compactibility and cheap 2. Binders can be added to the powder as a solution
- Main limitation: Some people intolerance to which is used as the agglomeration liquid during
lactose (lactose intolerance) wet granulation. This type of binder is sometimes
- Incompatible with some excipients such as referred to as the solution binder.
Magnesium stearate, amine drugs and strong 3. Binders can be added to the powder as a dry
oxidizers. powder which is mixed with the other ingredients
Note: if Lactose is employed as diluent, a lubricant must be before compaction or compression during
added as a lubricant (lubricant is required) to reduce slugging or tableting process. They are referred to
friction. as the dry binders/external binders
Starch Examples:
- Aside from being a diluent, it can also act as a 1. Starch paste
binder and disintegrants. 2. Povidone & copovidone
- Provides moisture balance to the formulation 3. Hydroxypropylmethylcellulose
- Stabilize the hygroscopic drugs 4. Carboxymethylcellulose
- Lactose is still more advantageous than starch. - Precaution/ care must be practice in using binders
Mannitol due to Difficulty encountered
- Sugar alcohols (glucose, sucrose, mannitol, xylitol
sorbitol) but mannitol is widely used among them DIFFICULTY ENCOUNTERED:
in chewable tablets because it produces a Inadequate binder Too much binders
negative heat of solution imparting a cooling (underwetting) (overwetting)
sensation.  Soft granules  Too hard tablets
- Alternative filler to lactose primarily used in  Too much fines  Difficulty in dry
lozenges and chewable tablets because they  Inadequately screening
provide pleasant taste hard tablets  Delayed dissolution
- The use of mannitol is limited only because it is & absorption
EXPENSIVE. DISINTEGRANTS
- Sugar free diluent: Xylitol (diluent of choice) - Ensure that the tablet, when in contact with a
Microcrystalline cellulose (MCC) liquid, breaks up into small fragments, which
- commonly employed or the diluent of choice for promotes rapid drug dissolution.
direct compression of tablets - Disintegrants promotes break-up of the particles
- Cellulose derivatives (eg. MCC) are
biocompatible, chemically-inert and possess good Mechanisms:
tablet forming and disintegrating property. 1. SWELLING
- Can also be use in wet granulation process - it promotes disruption or sorption of the water into
 The concentration of MCC used is at 5- the tablet causing rapturing of the tablet thus
15%; minimizing the tablet hardening and cause disintegration of the tablet.
reduces tablet mottling - Ex: Starch 10- 15% (act as a disintegrants via
- Disadvantage of MCC: swelling action)
1. It needs lubricant as the added 2. CAPILLARY ACTION
material/ingredient (same with lactose) - Uses capillary forces that sucks the water into the
2. It is expensive (same with mannitol) pores of the tablet
- Ex: Microcrystalline cellulose
3. DEFORMATION
- it deforms the tablet losing its rigidity and
integrity

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4. EFFERVESCENCE NON-ESSENTIAL TABLET EXCIPIENTS

- production of Carbon Dioxide gas (Smaller particle COLORANTS
size of the powder; the greater the effervescence; - Added to tablets to aid identification and patient
the greater its disintegration rate.) compliance.
- production of CO2 gas enhances the disintegrating - The appearance of the tablet is of great
action of the tablet importance to the way that is perceived by the
NOTE: patient.
Some examples of superdisintegrants are croscarmellose, - The microscopic appearance of the tablet like the
crospovidone, sodium starch glycolate, and magnesium shape, size, color and appearance of the tablet as
aluminum silicate well as the markings can all contribute to the
FLOW ACTIVATORS (ANTIFRICTIONALS) patients’ expectation of a medicine.
- The excipients are added prior to compression - The coloring of a tablet can be achieved via:
enhances the flow the powders/ granules into the 1. Incorporating a liquid dye or pigment into the
tablet and prevents sticking of powders into powder prior to compression
hopper of the machine. It constitutes 5-10% of flow 2. Applying colored coat to the tablet following
activator during the prior to compression. compression (after compression)
- For compression aid
- They enhance the flow of powders/granules into TYPES
the tablet die and prevent the sticking a. Liquid - Added to liquid d
SUBTYPES: dyes preparations
 Lubricants –decreases friction - Soluble forms of
 Glidants – improves flow particular color and
 Anti-adherent - reduces sticking goes into the solution
Note: these are added as a package (trio; sila tulo I add) that can result to a deep
*Powerpuff gals vibrant color.
- Concentration: 0.0005-
Most employed: 0.001 %
1. Magnesium  the most effective in all - Maximum: 0.3%
stearate 3 b. Lake - Dyes that undergo
 it can be: lubricant, pigments processing step that
glidant, and
- FD&C adheres into the
antiadherent
 However, incompatible - D&C insoluble substrates
with lactose, aspirin such as aluminum and
(ASA) and strong calcium salts;
oxidizer commonly used in tablet
2. Talc  Commonly used as a like chewable tablet and
glidant having the coating solution.
benefit of antiadherent - FD&C (colorants)- Food
3. Fumed silicon  Most effective glidant Drug and Cosmetics &
dioxide
- D&C (colorants)- Drug
- Aka Cabosil or
CAB-O-SIL and Cosmetics
4. Sodium  Offers hydrophilic c. External - Added to drugs &
benzoate advantage; increases D&C cosmetics for external
moisture content use
 It also enhances the - Not included, if the
compactibility/compre preparation is applied to
ssibility of the the lips/ other parts
powdered materials
cover with mucous
5. Colloidal silicon  Offers less dense
dioxide characteristics
membrane it should be
EXTERNAL D&C are not
recommended.

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- MethylEsterdipeptide of aspartic
acid and Phenylalanine
- It is contraindicated to patient
with Phenylketonuria (deficiency
in phenylalanine Hydroxylase) an
enzyme converts Phenylalanine to
Tyrosine.
- Symptoms:
1. Musky Odor sa breath/ urine
- 2. It may cause: Seizure or
Neurological disorder kay kulang
man og Tyrosine nga si
- Tyrosine precursor for bioamides.
Cyclamate - 2013- Banned to the market due
(magic sugar) to carcinogenic potential.
Acesulfame K - 130x sweeter than sucrose
- Commonly employed sugar in diet
soft drinks (eg. Diet coke, coke
zero)
Stevia powder - 30x sweeter than sucrose from:
Stevia Rebaudiana Plant
- Advantages:
1. Natural
2. Safe
3. Non-toxic
Mannitol - 70x sweeter than other
sweetening agents
TABLET COATING

 Reasons for coating tablets

FLAVORANTS
- Are incorporated into the formulation to give the 1. Protection of the drug from the environment for
tablet a more pleasant taste or mask the stability reasons.
unpleasant taste - Drugs are protected from environmental moisture
- Cam also be achieved via coating the tablet while in storage
Examples:
Drug Flavor a. Sugar Coated Tablet- to protect the drugs that is prone
1. Sweet - Honey, Mixed fruits, to oxidation.
Berries, Maple, Vanilla b. Enteric Coated Tablet- to protect the drugs from
2. Bitter - Chocolate, Anise, Cherry, premature distraction in the stomach.
Mint, Raspberry 2. Taste masking
3. Sour - Chocolate, Anise, Cherry, - Sugar coated tablet
Mint, Raspberry - there are drugs that are bitter-tasting, metal taste,
4. Salty - Butterscotch, Maple, acid/acrid taste therefore tablet coating is
Peach, Melon, Raspberry, employed to enhance palatability and for patient
Cinnamon, Orange compliance (especially pedia)
5. Metallic - Grape, Lemon, Lime 3. Minimizing patient/operator contact with the
6. Alkaline - Chocolate, Cream, drug substance, particularly for skin sensitive.
Vanilla, Mint - There are drugs that in handling, care must be
7. Oily - Chocolate, Cream, observed because when it come contacts the skin,
Vanilla, Mint it causes irritation therefore tablet coating is
- These flavorants can be employed in both solid employed for additional protection and avoid
and liquid preparations contaminants.
4. Improving product identity and appearance
Sweetening agents - Improves tablet profile (identification and
Sucrose - Most commonly used, the bench elegance)
work of sweetness of all the 5. Improving ease of swallowing
sweetening agent. 6. Improving mechanical resistance
Glycerin - Less sweet than sucrose - Ex: Film-coated tablets
Saccharin - 300x sweeter than sucrose & has 7. Modifying release properties-
bitter after taste * Example: Enteric Coated Tablet- Delayed release
Aspartame - 100-200x sweeter than sucrose properties.

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PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

 Main used methods to coat Pharmaceutical - STEPS: (5)

Tablets: Sugar, Film, Enteric & Compression a. Seal coating
Coating b. Subcoating
c. Smoothing
BASIC PROCESSES: d. Color coating
METHODS DESCRIPTION e. Polishing
Compression -For two incompatible drugs f. Imprinting (optional step)
coating
(tablet within a tablet)
-use in order to protect the core of the SUGAR COATING CAN BE DONE BY A NUMBER OF
tablet METHOD:
- It is a system in which the entire 1. PAN COATING
surface of an inner core is completely -most widely used
surrounded by the coat. 2. PAN SPRAYING
Pan coating -Employed for both sugar coating and
(commonly film coating
employed) -make use of coating pans with hot
and cold air-input system and
exhaust system for continuous
process to remove moisture and fine
powdered generated during the
coating operations. (avoid dusting or
mottling)
Air suspension -Most dependable method for
coating applying film coating
(commonly -the coating material is atomized and 3. PAN SUSPENSION
employed) apply to tablets as they are suspended
in the chamber. It is like a fluid-bed OVERVIEW OF THE PAN CPOATING PROCESS:
processing. A. Performed in coating pans in which tablets are
Dip coating -Tablets are placed in baskets and tumbled in three-dimensional direction and the
dipped into container of coating pan is supplied with a source of warm air for drying
solution and extraction system to remove moist air or dust.
-this method has not been widely B. Coating solution is ladled onto the tablet bed and
accepted because of the difficulty is distributed around for a period of time to allow
encountered during the coating the coating to dry before a further quantity of
procedure. solution is added.
C. Dusting powder (Ex. Calcium Carbonate, talc or
Disadvantage: acacia) may be sprinkled onto the surface of the
- Lack of coat uniformity tablets during the drying phase to prevent the
tablets from sticking together.
4 TYPES OF TABLET COATING: D. The cycle of wetting and drying is continued until
1. SUGAR COATING the desired amount of coating has been applied to
2. FILM COATING the tablets.
3. ENTERIC COATING

SUGAR COATING
- Involves coating tablets with water-soluble
sucrose-based solution which quickly dissolved
after swallowing.
- a highly skilled multi-step process that is very
labor-intensive and needs a skilled person.
- one of the skills needed in sugar coating adding
appropriate quantity of solution
- “IF TOO LITTLE QUANTITY IS ADDED, NOT ALL
TABLETS WILL PICK UP SOME OF THE COATING
AND UNEVEN DISTRIBUTION WILL RESULT”
- IF TOO MUCH QUANTITY IS ADDED, TABLETS WILL
STICK TOGETHER THUS EXPERTIES IN APPLYING
SUGAR COATING IS REQUIRED IN HANDLING
SUGAR COATING.

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Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

A. SEAL COATING - Smoothing coat: Simple Sucrose syrup (60%-

(SEAL COATING) (WATER-PROOFING) 70%) + Titanium dioxide (1-5%)
- For components that may be adversely affected by - Figure below: Adds bulk to the tablet; contains
moisture. colorants where applicable
- It is important that the coating does not penetrate
the core.
- Purpose: Separate water from the tablets core
- in order to strengthen the core.
Waterproofing substances: - After subcoating, 5-10 additional coating for
1. Shellac smoothing to complete the rounding off edges and
- Traditionally, Shellac dissolve in ethanol was smooth the coat.
applied and most popular but it was replaced by
the synthetic water-resistant polymers.
(CAP/PVAPS)
2. Zein
3. Cellulose acetate phthalate (CAP)
4. Polyvinyl acetate phthalate (PVAP
B. SUBCOATING
- The Subcoat is an adhesive coat on which the
third-layer (smoothing) coating can be applied
and provides rounding off.
- Most critical step in sugar coating since it serves
as the basis for elegant tablet profile.
- Significant increase in the tablet weight and
rounds off tablet edges to produce a smooth
surface.

- HAS COLORANTS ALREADY BUT ONLY MINIMAL

- If needed, about 3-5 subcoats of a sugar-based THAT IS WHY IT PROCEEDS TO COLORING STEP
syrup are applied. D. COLORING
- Significantly, during this coating process, it can - to attain final smoothness and appropriate color
increase the tablet weight for about 50% of the tablets, several coats of thin syrup
(minimum) on its original weight but some adds containing desired colorants are applied.
100% of the weight. - STEPS:
- After subcoating, dusting powders are also 1. Grossing- develops the color base
employed to help produce a hard coat and 2. Heavy syruping- built up solid color rapidly
prevent tacking/sticking of the tablets. 3. Regular syruping- final color and elegance
DUSTING POWDERS:
- CALCIUM CARBONATE E. POLISHING
- TALC
- To achieve the characteristic gloss or sheen of the
- ACACIA
tablet
- In large scale, with the aid of mechanical
SUBCOATING SOLUTION:
equipment; the tablets are transferred to the
- A mixture of sucrose solution + adhesive gum
POLISHING PAN and they are coated with
(gelatin or acacia)
beeswax and carnauba wax mixture.
C. SMOOTHING
- In small scale, tablets are simply wiped with cloth
(SYRUPING) ( COLORING) impregnated with beeswax or carnauba wax
- The smoothing coat consists of the majority of the mixture.
tablet bulk and provides the tablet with a smooth
F. IMPRINTING (OPTIONAL STEP)
finish.
- Embossed, debossed
- Smooth out the sub-coated surface and completes
- Commonly involved printing on the surface
the rounding off.

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Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

DISADVANTAGES (SUGAR-COATED TABLETS)

- Bulkier than the uncoated tablets
- Less durable
- Time consuming to prepare
- Requires expertise in applying
FILM COATING
- The coating process places a thin, skin light of a
plastic-like material over the compressed tablets.
- In contrast to sugar coating, the film-coating only
adds up to 5% weight of the final tablet and also
adds/increases the tablet thickness for about 2-
5% (negligible only)
- Involves the application of a polymer film to the
surface of the tablet.
- Advantage: No significant increase in tablet size
and weight

EQUIPMENTS EMPLOYED IN FILM-COATING: COMPONENTS:

MODIFIED CONVENTIONAL COATING PAN FILM–COATING IS DIVIDED INTO TWO:
- Limitations of conventional coating pan (original) 1. FUNCTIONAL COAT
 DRYING EFFICIENCY THAT EMPOSES - They are necessary to provide the purpose of film-
GREATER DEMAND AND POOR MIXING coating
EFFICIENCY THAT RESULTS IN DEAD  Film former
SPOTS IN THE TABLET BED.  Alloying substances
 Plasticizer
SIDE-VENTED PAN  Surfactant
- The most commonly used equipment for film-  Opaquant & colorant
coating 1. Film former
FLUID BED COATING (AIR SUSPENSION - Producing smooth thin films.
COATING) - Ex: Cellulose acetate phthalate (CAP)
- Offers an alternative to pan coating Polyvinyl acetate phthalate (PVAP)
- Particularly popular for coating a multi-particulate 2. Alloying substances
system in a dosage form -Providing water solubility or permeability to the film to
ensure penetration.
Ex: Polyethylene glycol (PEG)
3. Plasticizer
- Produce flexibility and elasticity of the coatings and
provide durability.
Ex: Castor oil, Glycerin, Phthalate esters
4. Surfactant
- Enhances spreadability of the film during application.
Ex: Polyethylene sorbitan derivatives
5. Opaquant & Colorant
- aesthetic appearance.
-Titanium dioxide (Opaquant)
-FD& C (Colorant)

2. NON-FUNCTIONAL COAT
- Are there just to provide elegance
- Pwede ran aa or wala sa formulation
 Glossant- added for luster appearance
Ex: Beeswax
 Sweetener
 Flavor
 Aroma
 Volatile solvents (mixture of acetone and
alcohol)

REMELLETE, LESLIE ANN T. 31

Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

COMMONLY USED POLYMERS

POLYMER COMMENTS COMMONLY USED ENTERIC COATING POLYMERS
Methylcellulose (MC) -Soluble in cold water, GI fluids and POLYMER SOLUBILITY COMMENTS
a range of organic solvents. Shellac ↑ pH 7 The original enteric
Ethylcellulose (EC) -Soluble in organic solvents, coating material,
insoluble in water and GI fluids. originally used in
-Used alone in modified release sugar-coated
formulations and in combination tablets. The high
with watersoluble celluloses for pH required for
immediate-release formulations. dissolution may
Hydroxyethylcellulose -Soluble in water and GI fluids delay drug release.
(HEC) Natural product
Methyl -Soluble in water and GI fluids. Has which exhibits
batch-to-batch
hydroxyethylcellulose similar film forming properties to
(MHEC) HPMC but is variability.
less soluble in organic solvents, Cellulose acetate ↑ pH 6 The high pH
which limited its popularity when phthalate (CAP) required for
solvent coating dissolution is a
was the norm. disadvantage.
Hydroxypropyl cellulose -Soluble in cold water, GI fluids and Forms brittle films,
(HPC) polar solvents. Becomes tacky so must be
when dried, so combined with
other polymers.
is unsuitable for use alone, often
used in combination with other Polyvinylacetate ↑ pH 5
polymers to phthalate (PVAP
optimize adhesion of coat. Hydroxypropyl ↑ pH 4.5 Optimal
Hydroxypropyl - Soluble in cold water, GI fluids, methylcellulose dissolution profile
methylcellulose (HPMC) alcohols and halogenated phthalate for enteric coating
hydrocarbons. (HPMCP)
-Excellent film former, and the most Polymers of Various grades available with dissolution
widely used polymer. Can be used methacrylic acid occurring above pH 6
with lactose to improve and its esters
adhesiveness.
Sodium -Soluble in water and polar solvents
carboxymethylcellulose COMPRESSION COATING
(NaCMC) - Similar to the preparation of multiple compressed tablets
having an inner core and outer shell of drug material.
Film-forming polymers - An anhydrous operation and thus may be safely
employed in the coating of tablets containing a drug that
- They constitute about 7-18% of the formulation for
is labile to moisture.
the film solution - Achieved by placing the core in a large die that already
Plasticizer contains some of the coating formulation.
- It constitutes 0.5 %- 2%
Colorants & Opacifier
- It constitutes 2.5%-8%
Vehicle
- [Link] (as much as is sufficient) to make 100%
particularly for aqueous film-coating formulation

ENTERIC COATING
- Design to resist the dissolution in the stomach but
dissolve less in acidic environment or usually in a pH of
4.8 or greater
- The design of enteric-coating may be:
1. Based on the transit time required for passage to the intestines
and may be accomplished through coating of sufficient thickness.
2. Based on factors of pH, resisting dissolution in the highly acid
environment of the stomach but yielding to the less
acid environment of the intestine.

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Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

COATING METHODS
METHODS ADVANTAGES DISADVATAGES
SUGAR - Elegant final product. - Long process time.
COATING - Tablets can be printed for - Traditional
identification purposes. manufacture
- Cheap, readily available more an art than a
starting materials. science; high operator
- Simple equipment dependency.
requirements. Significantly increases
- Excellent protection from tablet size.
environment
FILM- - Quick process, easy to Finish not as elegant as
COATING automate. sugar coating.
DUE TO EXCIPIENTS USED
- Negligible increase in tablet Picking -Small amount of film fragments flaking
size. Tablets can be Coating process stresses
identified either by printing tablet formulation, cores
from the tablet surface (punch)
or through intagliations. must be robust to resist Peeling- Large amounts of film fragments flaking
- Minimal effect on drug abrasion and edge
release. chipping during coating.
from the tablet surface
- Enteric coating feasible Orange peel- Roughness of the tablet surface due
COMPRESSION -It is a dry process, so suitable for -Significant increase in to failure of spray droplets to coalesce
COATING moisture sensitive tablet weight.
compounds. -Possible to produce Bridging- Filling-in of the score line or indented
-Can be used for combination tablets with no inner logo on the tablet by the film.
products where the active core
substances are incompatible.
DUE TO EXCIPIENTS USED

TABLET DEFECTS Tablet erosion- Disfiguration of the core tablet

Tablet defects Divided into 3: when subjected for too long in coating solution
1. Due to tableting process (coating or Sweating -Oil droplets
compression process) Blistering- Reduced adhesion between filling and
2. Due to excipient used surface of tablets due to rapid drying
Orange peel Blooming -Dull film due humid conditions or
- film-coating is an excipient but can be also due migration of plasticizers to surface of coat
to coating process Spotting - Due to migration of plasticizers, dyes
3. Due to more than 1 factor or other additives in the coating formulation.

DUE TO MORE THAN 1 FACTOR

Mottling- Uneven distribution of colors
Wrinkling -Caused by improper drying o film
former defect
Flaking- Removal of tablet surface
Weight Variation-Cause by poor mixing, unequal
length of lower punches, poor flow, size and
distribution of the granules being compressed.
Double impression- Involves only lower punches,
tablet receives the imprint of the punch.

DUE TO TABLETING PROCESS

Capping- The partial or complete separation of
the top or bottom of a tablet from the main body.
Lamination- Separation of tablet into two or more
distinct layer
Chipping- Removal of edges or small portion of
tablets ENCAPSULATION
Sticking- Adhesion of granulation to the die walls
1. Hard gelatin capsule
•Rigid two-piece capsules made from gelatin,
water and colorants.

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Pharmaceutics 2
PHARMACEUTICAL MANUFACTURING (WITH REGULATORY PHARMACY, QUALITY ASSURANCE AND CGMP)

Hard gelatin capsules are manufactured in two

sections, the capsule body and a shorter cap

Polishing & Cleaning

Salt polishing - uses NaCl crystals
Pan polishing -uses polyurethane or cheesecloth
Cloth dusting- rubbed with a cloth which is
impregnated with an inert oil
Brushing- uses soft brushes which are
accompanied by vacuuming.
2. Soft gelatin capsule
- Are made of gelatin to which glycerin or polyhydric
alcohol such as sorbitol or has been added to render
the capsule elastic or plastic like
Method:
1. Plate process
2. Rotary die process
3. Reciprocating die process

REMELLETE, LESLIE ANN T. 34